ImmunoPathology IIAutoimmune Diseases

R. Pat Bucy, MD, PhDProfessor of Pathology, Microbiology, and

Medicine

Organ Specific and Non-Organ Specific Autoimmune Diseases

Organ Specific Non-Organ Specific

Antigen Localized to given organ

Widespread throughout the body

LesionsAntigen in organ is target of immune attack

Immune Complex deposition in many tissues – skin, joints, kidney

Overlap With other organ specific diseases

With other non-organ specific diseases

Breaking ToleranceExperimental Induction of anti-self responses

• Conjugation of self epitopes to immunogenic determinants• Localization with another vigorous immune response• Exposure of "Hidden" self antigens• Genetic patterns of responsiveness

General SchemeInduction of Organ Specific Autoimmune Disease

• Induction of local immune response – Infection, Drug Rx, Trauma, etc

• Malfunction of immune regulation– Genetic predisposition

• Progressive immune response to tissue Ag – Epitope Spreading

• Tissue destruction and loss of function

Organ Specific Autoimmune Diseases• Endocrine

– Thyroiditis/Grave's Disease– Insulin Dependent Diabetes– Atrophic Gastritis/Pernicious

Anemia– Idiopathic Addison's Disease– Idiopathic Hypoparathyroidism– Idiopathic Hypogonadism– Idiopathic Hypophysitis

• Neuromuscular system– Multiple Sclerosis– Guillian-Barre (Idiopathic

Polyneuritis)– Myasthenia Gravis

• Joints– Rheumatoid arthritis– Relapsing Polychrondritis

• Gastrointestinal– Crohn's Disease– Ulcerative colitis– Primary Biliary Cirrhosis– Chronic Active Hepatitis

• Miscellaneous– Sjögren's Syndrome– Idiopathic myocarditis– Interstitial pneumonitis– Idiopathic Interstitial Nephritis– Lichen Planus– Bullous Skin Diseases

• Iatrogenic– Allo-Transplant rejection

Multiple Sclerosis

• Immune Destruction of CNS Myelin• Histopathology - Depends on stage of

lesion• Viral infection as Antecedent• Animal Models - EAE

Experimental autoimmune encephalomelitis (EAE)

Insulin Dependent Diabetes MellitusImmune mediated destruction of Islet b cells

• Histopathology• Epidemiology

– Viral Antecedent– MHC linkage

• Animal Models– BB rat– NOD mouse– low dose streptozoticin

Islets of Langerhans

Normal mouse NOD mouse with acute“insulitis”

Autoimmune Thyroiditis

• Lymphocytic (Hasimoto’s) Thyoiditis– Chronic inflammatory lesion that results in destruction

of follicles and ultimately hypothyriodism

• Grave’s Disease– Antibody to TSH Receptor that stimulates receptor

function and results in hyperthyroidism

Graves’ Disease

Myasthenia Gravis• Muscle weakness due to autoantibody to

acetylcholine receptor of neuromuscular junction

• Symptoms can be transferred with antibody to AchR

• Relationship to the Thymus

Myasthenia Gravis(Blocking auto-antibodies)

Inflammatory Bowel DiseaseTwo clinical entities with substantial overlap

• Crohn's Disease (Regional Enteritis)– Transmural inflammation– Occurs throughout GI tract, terminal ileum most

common– "Skip lesions" and granulomas common– Several new animal models

• Ulcerative Colitis– inflammation restricted to mucosa– involves contiguous areas in colon (may extend into

ileum)

Rheumatoid Arthritis• Chronic inflammatory disease of joint

synovium• Presence of Rheumatoid factor

– antibody to Fc of IgG usually of IgM class– form immune complexes but rarely result in

glomerulonephritis• Erosive lesions of cartilage and bone result

from inflammatory “pannus” • Can involve other organs besides joints• Occasionally associated with other

autoimmune syndromes

Rheumatoid Arthritis

Rheumatoid Nodule

Plasma cells in Rheumatoid synovitis

Rheumatoid Arthritis

Rheumatoid ArthritisSynovial erosions

Systemic Lupus Erythematosis

• Classic “Systemic” Autoimmune Disease• Mediated by immune complex injury

– DNA/anti-DNA immune complexes often implicated in tissue injury

• Animals models - genetic predisposition to immune complex formation and nephritis

• Variant forms of Lupus

Lupus Nephritis

A Focal Proliferative GNB Diffuse Proliferative GNC “wire loop” lesionsD Subendothelial ICE “Granular” pattern of IgG

Lupus skin Lesion

“butterfly” rash

General SchemeInduction of Organ Specific Autoimmune Disease

• Induction of local immune response – Infection, Drug Rx, Trauma, etc

• Malfunction of immune regulation– Genetic predisposition

• Progressive immune response to tissue Ag – Epitope Spreading

• Tissue destruction and loss of function

Time (days)

Act

ivity

anti-viral immune response

Viralinfection

Tissue Injury(auto-antigens)

auto-AgT cells

? Potential Hypersensitivity

Infection and Hypersensitivity

Memory

Time (days)

Act

ivity

anti-viral immune response

Viralinfection

Tissue Injury(auto-antigens)

auto-AgT cells

auto-AgRegulatory T

Infection and Hypersensitivity

Time (days)

Act

ivity

anti-viral immune response

Viralinfection

Tissue Injury(auto-antigens)

auto-AgT cells

? Potential Hypersensitivity

Infection and Hypersensitivity

Time (days)

Act

ivity

anti-viral immune response

Viralinfection

Tissue Injury(auto-antigens)

auto-AgT cells

AutoimmuneDisease

Infection and Hypersensitivity

Time (days)

Act

ivity

anti-viral immune response

Viralinfection

Tissue Injury(auto-antigens)

auto-AgT cells

? Potential Hypersensitivity

Infection and Hypersensitivity

Time (days)

Act

ivity

anti-viral immune response

Viralinfection

Tissue Injury(auto-antigens)

auto-AgT cells

Infection and Hypersensitivity

Time (days)

Act

ivity

anti-viral immune response

Viralinfection

Tissue Injury(auto-antigens)

auto-AgT cells

Contributors to control• Dynamics of infectious

organism• Frequencies and function of

autoreactive T cells• Cytokine milieu - TGFb +

IL-10 versus IL-6, TNFa, IFNg

• Amount and kinetic course of auto-Ag

Infection and Hypersensitivity

Overview of ImmunoPathology• Immune mechanisms that result in tissue injury• Classification by mechanism vs antigen source• Exogenous antigens

– Infectious Agents– Environmental Agents

• Iatrogenic – Solid organ transplants – Bone marrow transplants

• Neoplastic cells• Autoantigens

ImmunoPathology Lab Discussion

http://peir.path.uab.edu/iplab/